Improved Synthesis for the 4-Pyridone Intermediate of Baloxavir Marboxil: Elimination of Polar Aprotic Solvents and Optimization Through Design of Experiments (DoE)

This article presents the development of an improved synthetic process for a crucial intermediate in the production of the antiviral drug baloxavir marboxil. The focus is on optimizing the telescoped synthesis of methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)-amino)-4-oxo-1,4-dihydropyridine-2-carboxylate (compound 7) built on the original method, which used polar aprotic solvents to improve selectivity in the acid-catalyzed dehydration-condensation reaction between intermediate ester 6 and tert-butyl carbazate. This process encountered difficulties related to high-boiling solvent recovery and the generation of nitrogen-rich wastewater. To overcome these challenges, we evaluated three optimization strategies. Notably, the use of a PPTS-organic base buffering system (Strategy III) enabled the replacement of the polar aprotic solvent DMAc with readily recoverable THF under the acidity adjustment and Lewis base catalysis effect of triethylamine (TEA). Design of experiments (DoE) further optimized the reaction parameters, significantly reducing the level of impurities, including the identification of three previously unreported process impurities. The optimized process was successfully scaled up to 135 g in the laboratory, yielding the monohydrate form of compound 7 with a purity of 98.3% and an overall yield improved from 78.6% to 85.1%.